And if you only know Javascript, HTML, and CSS? If you don't already know something like Python (Django) or Ruby (RoR) or Java (Spring), wouldn't learning a whole new language in addition to another GUI API (like GTK+ or Qt) and execution model miss the point of it?

At least, with Node.JS, there are some alpha-quality GTK+ bindings in development if you really don't mind sacrificing the no-install benefits of an in-browser application.

Disclaimer: I may have the mindset of a UI/UX designer, but my primary language of choice is Python and I write both GTK+ apps and web apps using a variety of languages. I'm not a representative example and, in fact, I'm only starting to learn Node.JS because Socket.IO is much less effort than writing my own WebSockets fallback wrapper for select-based Python frameworks like Tornado.